Particle formation

ABSTRACT

Spray-coated pharmaceutical powder compositions for transdermal administration using a needleless syringe comprise seed particles coated with a pharmaceutical composition, the said coated seed particles having an average size of about 10 to 100 μm and having an envelope density ranging from about 0.1 to about 25 g/cm 3 .

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. provisional application serial No.60/102,726, filed Oct. 1, 1998, from which priority is claimed pursuantto 35 U.S.C. §119(e)(1) and which application is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The invention relates to a method for producing powdered pharmaceuticalcompositions. More specifically, the invention relates to a method forforming dense, substantially solid particles from pharmaceuticalcompositions, where the particulate compositions are particularlysuitable for transdermal particle delivery from a needleless syringesystem.

BACKGROUND

The ability to deliver pharmaceuticals through skin surfaces(transdermal delivery) provides many advantages over oral or parenteraldelivery techniques. In particular, transdermal delivery provides asafe, convenient and noninvasive alternative to traditional drugadministration systems, conveniently avoiding the major problemsassociated with oral delivery (e.g., variable rates of absorption andmetabolism, gastrointestinal irritation and/or bitter or unpleasant drugtastes) or parenteral delivery (e.g., needle pain, the risk ofintroducing infection to treated individuals, the risk of contaminationor infection of health care workers caused by accidental needle-sticksand the disposal of used needles).

However, despite its clear advantages, transdermal delivery presents anumber of its own inherent logistical problems. The passive delivery ofdrugs through intact skin necessarily entails the transport of moleculesthrough a number of structurally different tissues, including thestratum corneum, the viable epidermis, the papillary dermis, and thecapillary walls in order for the drug to gain entry into the blood orlymph system. Transdermal delivery systems must therefore be able toovercome the various resistances presented by each type of tissue. Inlight of the above, a number of alternatives to passive transdermaldelivery have been developed. These alternatives include the use of skinpenetration enhancing agents, or “permeation enhancers,” to increaseskin permeability, as well as non-chemical modes such as the use ofiontophoresis, electroporation or ultrasound. However, these alternativetechniques often give rise to their own unique side effects, such asskin irritation or sensitization. Thus, the spectrum of pharmaceuticalsthat can be safely and effectively administered using traditionaltransdermal delivery methods has remained limited.

More recently, a novel transdermal drug delivery system that entailsthe, use of a needleless syringe to fire powders (i.e., soliddrug-containing particles) in controlled doses into and through intactskin has been described. In particular, commonly owned U.S. Pat. No.5,630,796 to Bellhouse et al. describes a needleless syringe thatdelivers pharmaceutical particles entrained in a supersonic gas flow.The needleless syringe is used for transdermal delivery of powdered drugcompounds and compositions, for delivery of genetic material into livingcells (e.g., gene therapy) and for the delivery of biopharmaceuticals toskin, muscle, blood or lymph. The needleless syringe can also be used inconjunction with surgery to deliver drugs and biologics to organsurfaces, solid tumors and/or to surgical cavities (e.g., tumor beds orcavities after tumor resection). In theory, practically anypharmaceutical agent that can be prepared in a substantially solid,particulate form can be safely and easily delivered using such devices.

One particular needleless syringe generally comprises an elongatetubular nozzle having a rupturable membrane initially closing thepassage through the nozzle and arranged substantially adjacent to theupstream end of the nozzle. Particles of a therapeutic agent to bedelivered are disposed adjacent to the rupturable membrane and aredelivered using an energizing means which applies a gaseous pressure tothe upstream side of the membrane sufficient to burst the membrane andproduce a supersonic gas flow (containing the pharmaceutical particles)through the nozzle for delivery from the downstream end thereof Theparticles.can thus be delivered from the needleless syringe at deliveryvelocities of between Mach 1 and Mach 8 which are readily obtainableupon the bursting of the rupturable membrane.

Another needleless syringe configuration generally includes the sameelements as described above, except that instead of having thepharmaceutical particles entrained within a supersonic gas flow, thedownstream end of the nozzle is provided with a bistable diaphragm whichis moveable between a resting “inverted” position (in which thediaphragm presents a concavity on the downstream face to contain thepharmaceutical particles) and an active “everted” position (in which thediaphragm is outwardly convex on the downstream face as a result of asupersonic shockwave having been applied to the upstream face of thediaphragm). In this manner, the pharmaceutical particles containedwithin the concavity of the diaphragm are expelled at a supersonicinitial velocity from the device for transdermal delivery thereof to atargeted skin or mucosal surface.

Transdermal delivery using either of the above-described needlelesssyringe configurations is carried out with particles having anapproximate size that generally ranges between 0.1 and 250 μm. For drugdelivery, an optimal particle size is usually at least about 10 to 15 μm(the size of a typical cell). For gene delivery, an optimal particlesize is generally substantially smaller than 10 μm. Particles largerthan about 250 μm can also be delivered from the device, with the upperlimitation being the point at which the size of the particles wouldcause untoward damage to the skin cells. The actual distance which thedelivered particles will penetrate depends upon particle size (e.g., thenominal particle diameter assuming a roughly spherical particlegeometry), particle density, the initial velocity at which the particleimpacts the skin surface, and the density and kinematic viscosity of theskin In this regard, optimal particle densities for use in needlelessinjection generally range between about 0.1 and 25 g/cm³, preferablybetween about 0.8 and 1.5 g/cm³, and injection velocities generallyrange between about 100 and 3,000 m/sec.

SUMMARY OF THE INVENTION

It is a primary object of the invention to provide a spray-coated powdercomposition for administration from a needleless syringe. It is also aprimary object of the invention to provide suitable spray-coatingmethods for producing such powder compositions.

In one aspect of the invention, a spray-coated powder composition foradministration from a needleless syringe is provided. The powdercomposition is formed from seed particles that are coated with anaqueous pharmaceutical composition. More especially, the spray-coatedpowder composition comprises seed particles coated with a pharmaceuticalcomposition, the said coated seed particles having an average size ofabout 10 to 100 μm and having an envelope density ranging from about 0.1to about 25 g/cm³.

The coated seed particles can have an average size of about 20 to 70 μm.Preferably, they have an envelope density ranging from about 0.8 toabout 1.5 g/cm³. The coated seed particles typically have asubstantially spherical aerodynamic shape and/or a substantiallyuniform, nonporous surface. The powders may also be characterized inthat the coated seed particles have a pharmaceutical composition loadingof about 1 to 50 wt %. The spray-coated powder compositions can contain,as the active pharmaceutical agent, any small molecule drug substance,organic or inorganic chemical, vaccine, or peptide (polypeptide and/orprotein) of interest.

In another aspect of the invention, a method for preparing thespray-coated powder composition is provided. The method comprisesspray-coating an aqueous pharmaceutical composition onto seed particlesunder conditions sufficient to provide coated particles having anaverage size of about 10 to 100 μm and an envelope density ranging fromabout 0.1 to about 25 g/cm³. In one particular embodiment, the methodentails the steps of: (a) suspending the seed particles in a reactionchamber using a hot air flow; (b) atomizing an aqueous pharmaceuticalcomposition into a fine spray and introducing the spray into thereaction chamber; (c) allowing the spray to spread over the surface ofthe suspended seed particles to coat them with a thin film; and then (d)drying the coated seed particles. If desired, the aqueous pharmaceuticalcomposition can be sprayed into the reaction chamber in a direction thatis transverse to the direction of the hot air flow.

It is an advantage of the invention that free-flowing powdercompositions can be produced having well defined particle size, densityand mechanical properties which collectively are suitable fortransdermal delivery from a needleless syringe. Further advantages ofthe methods of the invention include flexible pharmaceutical loading (upto about 50 wt %), overall process efficiency (no need forpost-formulation fractionation, classification or sieving operations),and the methods are readily scalable. The invention further provides:

a dosage receptacle for a needleless syringe, said receptacle containinga therapeutically effective amount of a spray-coated powder compositionof the invention; and

a needleless syringe which is loaded with such a powder composition.

These and other objects, aspects, embodiments and advantages of thepresent invention will readily occur to those of ordinary skill in theart in view of the disclosure herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified compositions or process parameters as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments of the inventiononly, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a particle” includes a mixture of two or more suchparticles, reference to “an excipient” includes mixtures of two or moresuch excipients, and the like.

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although a number ofmethods.and materials similar or equivalent to those described hereincan be used in the practice of the present invention, the preferredmaterials and methods are described herein.

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

By “transdermal delivery,” applicant intends to include both transdermal(“percutaneous”) and transmucosal routes of administration, i.e.,delivery by passage of a drug or pharmaceutical agent through the skinor mucosal tissue. See, e.g., Transdermal Drug Delivery: DevelopmentalIssues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker,Inc., (1989); Controlled Drug Delivery. Fundamentals and Applications,Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and TransdermalDelivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.), CRC Press,(1987).

As used herein, the term “pharmaceutical” or “pharmaceutical agent”intends any compound or composition of matter which, when administeredto an organism (human or animal) induces a desired pharmacologic and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, as well as biopharmaceuticals including molecules such aspeptides, hormones, nucleic acids, gene constructs and the like. Moreparticularly, the term “pharmaceutical” or “pharmaceutical agent”includes compounds or compositions for use in all of the majortherapeutic areas including, but not limited to, anti-infectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;local and general anesthetics; anorexics; antiarthritics; antiasthmaticagents; anticonvulsants; antidepressants; antihistamines;anti-inflammatory agents; antinauseants; antineoplastics; antipruritics;antipsychotics; antipyretics; antispasmodics; cardiovascularpreparations (including calcium channel blockers, beta-blockers,betaagonists and antiarrythmics); antihypertensives; diuretics;vasodilators; central nervous system stimulants; cough and coldpreparations; decongestants; diagnostics; hormones; bone growthstimulants and bone resorption inhibitors; immunosuppressives; musclerelaxants; psychostimulants; sedatives; tranquilizers; therapeuticproteins (e.g., antigens, antibodies, growth factors, cytokines,interleukins, lymphokines, interferons, enzymes, etc.), peptidesand-fragments thereof (whether naturally occurring, chemicallysynthesized or recombinantly produced); and nucleic acid molecules(polymeric forms of two or more nucleotides, either ribonucleotides(RNA) or deoxyribonucleotides (DNA) including both double- andsingle-stranded molecules, gene constructs, expression vectors,antisense molecules and the like).

The above pharmaceuticals or pharmaceutical agents, alone or incombination with other agents, are typically prepared as pharmaceuticalcompositions which can contain one or more added materials such ascarriers, vehicles, and/or excipients. “Carriers,” “vehicles” and“excipients” generally refer to substantially inert materials which arenontoxic and do not interact with other components of the composition ina deleterious manner. These materials can be used to increase the amountof solids in particulate pharmaceutical compositions. Examples ofsuitable carriers include water, silicone, gelatin, waxes, and likematerials. Examples of normally employed “excipients,” includepharmaceutical grades of carbohydrates including monosaccharides,disaccharides, cyclodextrans, and polysaccharides (e.g., dextrose,sucrose, lactose, trehalose, raffinose, mannitol, sorbitol, inositol,dextrans, and maltodextrans); starch; cellulose; salts (e.g. sodium orcalcium phosphates, calcium sulfate, magnesium sulfate); citric acid;tartaric acid; glycine; high molecular weight polyethylene glycols(PEG); Pluronics; surfactants; and combinations thereof. Generally, whencarriers and/or excipients are used, they are used in amounts rangingfrom about 0.1 to 99 wt % of the pharmaceutical composition.

The terms “individual” and “subject” are used interchangeably herein torefer to any member of the subphylum cordata, including, withoutlimitation, humans and other primates, including non-human primates suchas chimpanzees and other apes and monkey species; farm animals such ascattle, sheep, pigs, goats and horses; domestic mammals such as dogs andcats; laboratory animals including rodents such as mice, rats and guineapigs; birds, including domestic, wild and game birds such as chickens,turkeys and other gallinaceous birds, ducks, geese, and the like. Theterms do not denote a particular age. Thus, both adult and newbornindividuals are intended to be covered. The methods described herein areintended for use in any of the above vertebrate species, since theimmune systems of all of these vertebrates operate similarly.

The term “powder,” as used herein, refers to a composition that consistsof substantially solid particles that can be delivered transdermallyusing a needleless syringe device. The particles that make up the powdercan be characterized on the basis of a number of parameters including,but not limited to, the average particle size, the average particledensity, particle morphology (e.g., particle aerodynamic shape andparticle surface characteristics), and particle penetration energy(P.E.).

The average particle size of the powders produced according to thepresent invention can vary widely and is generally between about 10 and100 μm, more typically between about 20 and 70 μm. The average particlesize of the powder can be measured as a mass mean aerodynamic diameter(MMAD) using conventional techniques such as microscopic techniques(where particles are sized directly and individually rather than groupedstatistically), absorption of gasses, permeability or time of flight. Ifdesired, automatic particle-size counters can be used (e.g., AerosizerCounter, Coulter Counter, HIAC Counter, or Gelman Automatic ParticleCounter) to ascertain the average particle size.

Actual particle density, or “absolute density,” can be readilyascertained using known quantification techniques such as heliumpycnometry and the like. Alternatively, envelope (“tap”)density.measurements can be used to assess the density of a particulatepharmaceutical composition produced according to the methods of theinvention. Envelope density information is particularly useful incharacterizing the density of objects of irregular size and shape.Envelope density is the mass of an object divided by its volume, wherethe volume includes that of its pores and small cavities but excludesinterstitial space. A number of methods of determining envelope densityare known in the art, including wax immersion, mercury displacement,water absorption and apparent specific gravity techniques. A number ofsuitable devices are also available for determining envelope density,for example, the GeoPyc™ Model 1360, available from the MicromeriticsInstrument Corp. The difference between the absolute density andenvelope density of a sample pharmaceutical composition providesinformation about the sample's percentage total porosity and specificpore volume.

Particle morphology, particularly the aerodynamic shape of a particle,can be readily assessed using standard light microscopy. It is preferredthat the particles which make up the instant powders have asubstantially spherical or at least substantially elliptical aerodynamicshape. It is also preferred that the particles have an axis ratio of 3or less to avoid the presence of rod- or needle-shaped particles. Thesesame microscopic techniques can-also be used to assess the particlesurface characteristics, e.g., the amount and extent of surface voids ordegree of porosity.

Particle penetration.energies can be ascertained using a number ofconventional techniques, for example a metallized film P.E. test.

B. General Methods

In one embodiment, a powdered pharmaceutical composition is provided,wherein the powder composition (which is comprised of particles) isproduced using a spray-coating technique. The powders are suitable fortransdermal administration from a needleless syringe delivery system,and as such, the particles which make up the powdered composition musthave sufficient physical strength to withstand sudden acceleration toseveral times the speed of sound and the impact with, and passagethrough, the skin and tissue. The particles are formed by spray-coatingan aqueous pharmaceutical composition onto suitable seed particles. Theparticles can be delivered from a needleless syringe system such asthose described in commonly owned International Publication Nos. WO94/24263, WO 96/04947, WO 96/12513, and WO 96/20022, all of which areincorporated herein by reference.

The aqueous pharmaceutical compositions can contain, as the activepharmaceutical agent, any small molecule drug substance, organic orinorganic chemical, vaccine, or peptide (polypeptide and/or protein) ofinterest. In particular embodiments, the pharmaceutical agent is abiopharmaceutical preparation of a peptide, polypeptide, protein or anyother such biological molecule. Exemplary peptide and proteinformulations include, without limitation, insulin; calcitonin;octreotide; endorphin; liprecin; pituitary hormones (e.g., human growthhormone and recombinant human growth hormone (hGH and rhGH), HMG,desmopressin acetate, etc); follicle luteoids; growth factors (such asgrowth factor releasing factor (GFRF), somatostatin, somatotropin andplatelet-derived growth factor); asparaginase; chorionic gonadotropin;corticotropin (ACTH); erythropoietin (EPO); epoprostenol (plateletaggregation inhibitor); glucagon; interferons; interleukins; menotropins(urofollitropin, which contains follicle-stimulating hormone (FSH); andluteinizing hormone (LH)); oxytocin; streptokinase; tissue plasminogenactivator (TPA); urokinase; vasopressin; desmopressin; ACTH analogues;angiotensin II antagonists; antidiuretic hormone agonists; bradykininantagonists; CD4 molecules; antibody molecules and antibody fragments(e.g., Fab, Fab₂, Fv and sFv molecules); IGF-1; neurotrophic factors;colony stimulating factors; parathyroid hormone and agonists;parathyroid hormone antagonists; prostaglandin antagonists; protein C;protein S; renin inhibitors; thrombolytics; tumor necrosis factor (TNF);vaccines (particularly peptide vaccines including subunit and syntheticpeptide preparations); vasopressin antagonists analogues; and α-1antitrypsin. Additionally, nucleic acid preparation, such as vectors orgene constructs for use in subsequent gene delivery, can be used.

The pharmaceutical agent is typically prepared as an aqueouspharmaceutical composition using a suitable aqueous carrier, along withsuitable excipients, protectants, solvents, salts, surfactants,buffering agents and the like. Suitable excipients can includefree-flowing particulate solids that do not thicken or polymerize uponcontact with water, which are innocuous when administered to anindividual, and do not significantly interact with the pharmaceuticalagent in a manner that alters its pharmaceutical activity. In general,excipients which are sticky, or have high hygroscopicity are avoidedparticularly for powder formulations where the pharmaceutical is loadedonto the seed particle at a high concentration (e.g., >10 wt %).Examples of normally employed excipients include, but are not limitedto, pharmaceutical grades of dextrose, sucrose, lactose, trehalose,mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium orcalcium phosphates, calcium carbonate, calcium sulfate, sodium citrate,citric acid, tartaric acid, glycine, high molecular weight polyethyleneglycols (PEG), and combinations thereof. Suitable solvents include, butare not limited to, methylene chloride, acetone, methanol, ethanol,isopropanol and water. Generally pharmaceutically acceptable saltshaving Molarities ranging from about 1 mM to 2M can be used.Pharmaceutically acceptable salts include, for example, mineral acidsalts such as hydrochlorides, hydrobromides, phosphates, sulfates, andthe like; and the salts of organic acids such as acetates, propionates,malonates, benzoates, and the like. A thorough discussion ofpharmaceutically acceptable excipients, vehicles and auxiliarysubstances is available in REMINGTON'S PHARMACEUTICAL SCIENCES (MackPub. Co., N.J. 1991), incorporated herein by reference.

The seed particles can be comprised of any parenterally acceptablepowder (e.g., crystalline or amorphous), are selected to have goodflowability (i.e., are fluidizable), and are sufficiently dense forefficient use with needleless transdermal delivery systems. Crystallineparticles are generally preferred due to their inherently high particledensity and overall penetration energy. Seed particles having an overallspherical or at least elliptical shape are preferred. Particlesgenerally are selected to have an axis ratio of 3 or less, for example 2or less or 1.5 or less, in order to avoid rod- or needle-shapedparticles which are difficult to reprocess and are generally lessflowable.

Suitable seed particles can be comprised of any pharmaceuticallyacceptable carbohydrate (e.g., sugars such as lactose, mannitol,trehalose, etc.), polysaccharide, starch, biodegradable polymer (e.g.PLGA, a copolymer of L-lactic acid and glycolic acid), or the like. Theseed particles can have an average size of about 5 to 100 μm, forexample about 10 to 95 μm or about 20 to 70 μm. Seed particlepreparations having a substantially homogenous average particle size,can be readily obtaining using standard sieving or other particleclassification methodologies.

The spray-coated powders can be formed using any standard spray-coatingprocessing apparatus. In this regard, batch-type fluid-bed processorshave long been used to perform drying, granulation, and coatingoperations in the pharmaceutical industry for preparing solid dosageforms. Olsen, K. W. (1989) “Batch fluid-bed processing equipment: Adesign overview,” Part I., Pharm. Technol. 13:34-46, Olsen, K. W. (1989)“Batch fluid-bed processing equipment: A design overview,” Part II.,Pharm. Technol. 13:39-50. With the advent of the Wüirster spray coater,seed particles as small as 50 μm in size can, at least in theory, becoated. Iyer et al. (1993), Drug Devel. Ind. Pharm. 19:981-989. However,to date, the spray coating of seed particles having an average size of100 μm or less has been limited, particularly for protein or peptidepharmaceuticals. Maa et al. (1996) Intl. J. Pharmaceutics 144:47-59.

Spray coating processors that can fluidize seed particles of 10 μm orlarger, for example 20 μm and larger, and which can atomize a fine spray(droplet size of 30 μm or less, preferably 10 μm or less) are preferred.Suitable processors include any commercially available Wüirster spraycoater, or Wüirster HS spray coater (available from Glatt AirTechniques, Inc.). For fluid-bed processing, the spray coating processorcan utilize any suitable spraying method which is selected inconsideration of the desired characteristics for the finished product.These spraying methods (e.g., top, bottom or tangential (rotary coater))are generally known to those skilled in the art.

The liquid delivery system for the spray coat processor typicallyutilizes a binary nozzle, where the aqueous pharmaceutical compositionis supplied at a relatively low pressure through an orifice and isatomized by air. Pneumatic nozzles can be used to produce smallerdroplets. The atomization conditions, including atomization gas flowrate, atomization gas pressure, liquid flow rate, etc., can becontrolled to produce droplets from the pharmaceutical compositionhaving an average diameter of about 30 μm or less, with droplets havingan average size of 10 μm or less being preferred. Typically, theatomizing air pressure, liquid flow rate and the fluidizing airtemperature and volume are the most significant process variables andhave the greatest effect over the particle characteristics of theresultant coated particles. Drying temperature conditions of about50-150° C. inlet temperature and about 30-100° C. outlet temperature arepreferred. The thickness of the pharmaceutical coat can be controlled bythe drying time, and the present methods can provide spray-coatedpowders formed from seed particles loaded with from about 1 to 50 wt %(e.g., about 0.5 to 15 wt % of active pharmaceutical agent incompositions containing both active pharmaceutical agent and carrier),preferably >10 wt % of the aqueous pharmaceutical composition.

If desired, a secondary coating process can be used to provide furtherstructural integrity in the coated particles, for example, where thespray-coated powder particles are coated with a standard sugar excipientusing the same sort of spray-coating procedure as described hereinabove. In some cases, it may be desirable to coat the spray-coatedpowder particles with the same sugar used as the seed (e.g., mannitol,lactose, trehalose, or the like). Other secondary coating materialsinclude, but are not limited to, pharmaceutical grades of carbohydratesincluding monosaccharides, disaccharides, cyclodextrans, andpolysaccharides (e.g., dextrose, sucrose, raffinose, mannose, sorbitol,inositol, dextrans, and maltodextrans); starch; cellulose; salts (e.g.sodium orcalcium phosphates, calcium sulfate, magnesium sulfate); citricacid; tartaric acid; glycine; high molecular weight polyethylene glycols(PEG); Pluronics; surfactants; and combinations thereof. The secondarycoating material can also be used to optimize the particles for deliveryto mucosal target surfaces (e.g., by coating the spray-coated powderparticles with a lipid), or to alter or retard solubilitycharacteristics of the particles after delivery into an aqueousenvironment (e.g., by applying a secondary coating containing a salt,starch, dextran, or the like).

The spray-coating methods of the present invention can be used toproduce powders that are suitable for transdermal delivery from aneedleless syringe delivery device. Typical powders are characterized inthat the individual particles have an average size in the range of about20 to 70 μm, an envelope density ranging from about 0.1 to about 25g/cm³, preferably ranging from about 0.8 to about 1.5 g/cm³, and have asubstantially spherical aerodynamic shape with a substantially uniform,nonporous surface.

The particles which make up the spray-coated powders of the presentinvention will also have a particle penetration energy suitable fortransdermal delivery from a needleless syringe device. Such penetrationenergies can conveniently be assessed using a metallized film P.E.measuring procedure as follows: A metallized film material (e.g., a 125μm polyester film having a 350 Å layer of aluminum deposited on a singleside) is used as a substrate into which the powder is fired from aneedleless syringe (e.g., the needleless syringe described in U.S. Pat.No. 5,630,796 to Bellhouse et al.) at an initial velocity of about 100to 3000 m/sec. The metallized film is placed, with the metal coated sidefacing upwards, on a suitable surface. A needleless syringe loaded witha spray-coated powder produced according to the methods of the inventionis placed with its spacer contacting the film, and then fired. Residualpowder is removed from the metallized film surface using a suitablesolvent. Penetration energy is then assessed using a BioRad Model GS-700imaging densitometer to scan the metallized film, and a personalcomputer with a SCSI interface and loaded with MultiAnalyst software(BioPad) and Matlab software (Release 5.1, The MathWorks, Inc.) is usedto assess the densitometer reading. A program is used to process thedensitometer scans made using either the transmittance or reflectancemethod of the densitometer. The penetration energy of the spray-coatedpowders should be equivalent to, or better than that of reprocessedmannitol particles of the same size (mannitol particles that arefreeze-dried, compressed, ground and sieved according to the methods ofcommonly owned International Publication No. WO 97/48485, incorporatedherein by reference).

Once produced, the spray-coated powders of the present invention can bepackaged in individual unit dosages. As used herein, a “unit dosage”intends a dosage receptacle containing a therapeutically effectiveamount of a spray-coated pharmaceutical produced according to themethods of the present invention. The dosage receptacle is generally onewhich fits within a needleless syringe device to allow for transdermaldelivery from the device. Such receptacles can be capsules, foilpouches, sachets, cassettes, or the like.

C. EXPERIMENTAL

Below are examples of specific embodiments for carrying out the methodsof the present invention. The examples are offered for illustrativepurposes only, and are not intended to limit the scope of the presentinvention in any way.

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures, etc.), but some experimental error anddeviation should, of course, be allowed for.

EXAMPLE 1

The following spray-coated powder formulations are made using themethods of the present invention.

Formulation 1

Seed particles: 500 grams of lactose (Pharmatose, 100M & 200M, Crompton& Knowle), sieved to provide an average particle size of 20-75 μm by jetsieve.

Aqueous pharmaceutical composition: Lysozyme (5.0%) and trehalose (50%)at a total solid concentration of 20%.

Spray coater: GPCG-1 (Glatt Air), operated at the following coatingconditions: air inlet temperature=85° C., air outlet temperature=42° C.,liquid feed=15 mL/min, air velocity in the bed=3.5 m/sec., coatingloading 10% of lysozyme, and a coating time=35 min.

Formulation 2

Seed particles: 300 grams of lactose (Pharmatose, 100M & 200M, Crompton& Knowle), sieved to provide an average particle size of 20-75 μm by jetsieve.

Aqueous pharmaceutical composition: s-Calcitonin (20%), mannitol (30%),and trehalose (50%) at a total solid concentration of 10%.

Spray coater: Precision coater (MP-1, Niro), operated at the followingcoating conditions: air inlet temperature=68° C., air outlettemperature=34° C., liquid feed=12 mL/min, air velocity in the bed=3.5m/sec., coating loading 5% of s-Calcitonin, and a coating time=63 min.

Formulation 3

Seed particles: 300 grams of mannitol (Merck), sieved to provide anaverage particle size of 20-75 μm by jet sieve.

Aqueous pharmaceutical composition: recombinant human growth hormone(rhGH) (50%), mannitol (20%), glycine (10%), and trehalose (20%) at atotal solid concentration of 10%.

Spray coater: Precision coater (MP-1, Niro), operated at the followingcoating conditions: air inlet temperature=75° C., air outlettemperature=40° C., liquid feed=13 mL/min, air velocity in the bed=3.5m/sec., coating loading 5% of rhGH, and a coating time=24 min.

Formulation 4

Seed particles: 500 grams of mannitol (Merck), sieved to provide anaverage particle size of 20-75 μm by jet sieve.

Aqueous pharmaceutical composition: Bovine serum albumin (BSA) (100%) ata total solid concentration of 10%.

Spray coater: GPCG-1 (Glatt Air), operated at the following coatingconditions: air inlet temperature=85° C., air outlet temperature=42° C.,liquid feed=15 mL/min, air velocity in the bed=3.5 m/sec., coatingloading 15% of BSA, and a coating time=50 min.

Formulation 5

Seed particles: 300 grams of lactose (Pharmatose, 100M & 200M, Crompton& Knowle), sieved to provide an average particle size of 20-75 μm by jetsieve.

Aqueous pharmaceutical composition: Diphtheria toxoids vaccine (DPT)(2%), mannitol (30%), glycine (8%), and trehalose (60%) at a total solidconcentration of 10%.

Spray coater: Precision coater (MP-1, Niro), operated at the followingcoating conditions: air inlet temperature=75° C., air outlettemperature=40° C., liquid feed=13 mL/min, air velocity in the bed=3.5m/sec., coating loading 0.5% of DPT, and a coating time=58 min.

The spray-coated powder formulation of each Example is suitable fortransdermal administration from a needleless syringe and ischaracterized in that the individual spray-coated particles have anaverage size in the range of about 20 to 70 μm, an envelope densityranging from about 0.1 to about 25 g/cm³, preferably ranging from about0.8 to about 1.5 g/cm³, and have a substantially spherical aerodynamicshape with a substantially uniform, nonporous surface.

Accordingly, novel spray-coated powder compositions, and methods forproducing these compositions have been described. Although preferredembodiments of the subject invention have been described in some detail,it is understood that obvious variations can be made without departingfrom the spirit and the scope of the invention as defined by theappended claims.

What is claimed is:
 1. A spray-coated powder composition foradministration from a needleless syringe, said powder compositioncomprising seed particles coated with a pharmaceutical composition, thesaid coated seed particles having an average size of about 10 to 100 μmand having an envelope density ranging from about 0.1 to about 25 g/cm³and an axis ratio of 3 or less.
 2. The powder composition of claim 1,wherein said seed particles are crystalline particles.
 3. The powdercomposition of claim 1, wherein the seed particles have an axis ratio of2 or less.
 4. The powder composition of claim 1, wherein the seedparticles are selected from the group consisting of lactose, mannitol,trehalose, polysaccharides, starches, and biodegradable polymers.
 5. Thepowder composition of claim 1, wherein said coated seed particles havean average size of about 20 to 70 μm.
 6. The powder composition of claim1, wherein said coated seed particles have an envelope density rangingfrom about 0.8 to about 1.5 g/cm³.
 7. The powder composition of claim 1,wherein said coated seed particles have a substantially sphericalaerodynamic shape.
 8. The powder composition of claim 1, wherein saidcoated seed particles have a substantially uniform, nonporous surface.9. The powder composition of claim 1, wherein said coated seed particleshave a pharmaceutical composition loading of about 1 to 50 wt %.